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HIV-1 GP41 neutralization domain and use thereof

a technology of neutralization domain and hiv-1, which is applied in the field of hiv-1 gp41 neutralization domain, can solve the problems of poor immunogenicity, region would not be a useful vaccine target, and the inability of most individuals to produce similar antibodies with hiv-neutralizing properties

Inactive Publication Date: 2013-07-02
RUTGERS THE STATE UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The MDER peptide or antibodies recognizing it can neutralize resistant HIV-1 isolates with high efficacy, providing broad protection and reducing the likelihood of HIV infection and transmission, as demonstrated by its ability to induce potent neutralizing antibodies in preclinical studies.

Problems solved by technology

The predominant disadvantage of these epitopes is that they are poorly immunogenic.
It has been suggested that this autoreactive property accounts for the inability of most individuals to produce similar antibodies with HIV-neutralizing properties.
The lack of neutralizing activity of the previously described monoclonal antibodies and Fabs suggests that these reagents would not be useful in the neutralization of HIV and that therefore this region would not be a useful vaccine target.
However, neutralizing antibodies to each region are not provided.

Method used

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  • HIV-1 GP41 neutralization domain and use thereof
  • HIV-1 GP41 neutralization domain and use thereof
  • HIV-1 GP41 neutralization domain and use thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

Neutralizing Activity of 53M Serum Samples

[0053]Studies were conducted on two sets of Envs and sera isolated from a cohort in Zambia (Li, et al. (2006) J. Virol. 80:5211-18). Sera samples 53M and 133M both possessed high autologous neutralizing titers, but while 133M serum did not neutralize any of the heterologous Envs, 53M serum also had a lower neutralizing activity for a number of additional primary Envs. To map the general location of the autologous neutralization targets in 53M Env, a series of recombinants was generated in which various domains were exchanged between 53M Env and 133M Env, a second primary clade C Env that was resistant to neutralization by 53M serum (FIG. 1). This approach utilized conveniently placed restriction sites present in the conserved regions following the V2 (BglII) and V5 (MfeI) domains, resulting in the generation of infectious recombinant Envs in which N-terminal gp120 domain (through C2, including V1 / V2), C-terminal gp120 domains (V3-V5) and gp4...

example 2

Localization of gp41 Sequence that Mediates Autologous Neutralization

[0057]To identify the location of the epitope(s) responsible for the autologous neutralizing activity of 53M serum, the gp41 ectodomain sequences of six subtype isolates were analyzed to identify a sequence distinct from the other sequences. One particular region in the HR2 region was notably polymorphic, and the 53M sequence contained several charged resides that were unique for this sequence (indicated by the box in FIG. 2). This sequence was located approximately in the middle of the HR2 domain, and N-terminal to the MPER epitopes recognized by monoclonal antibodies 2F5 and 4E10.

[0058]To determine whether this region participated in the 53M gp41 neutralization epitope, several mutations were introduced at the polymorphic positions of this region in the chimeric Env that contained the gp41 region of 53M Env in the 133M Env background (p1666 in FIG. 1). The use of this chimeric Env allowed the isolation of the 53M...

example 3

Neutralization Sensitivity of Mutant 135M Env to 53M Serum

[0060]To further confirm the role of the region in HR2 identified as a neutralization determinant, it was determined whether substituting sequences from this region into a resistant Env could introduce neutralization sensitivity to 53M serum. The HR2 sequence of the 135M Env was the most closely related to that of 53M, so 135M Env was selected as the recipient. Six positions in the 640-655 region of HR2 differed in sequence for 53M and 135M Envs; Lys vs. Asp at 640, Glu-Lys vs. Thr-Glu at 647 / 648, Asn vs. Ser at 651 and Glu-Glu vs. Asp-Lys at 654 / 655 (FIG. 4). The first four of these changes were introduced into 135M Env resulting in a 135M (K / EK / N) mutant, and the effect on neutralization by 53M was examined. As shown in FIG. 5, mutating these four residues in the autologous 135M Env resulted in sensitization to 53M serum. Whereas the parental virus was not neutralized at serum dilutions of 1:100 or 1:20, the mutant was neut...

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Abstract

The invention relates to isolated monoclonal antibodies which specifically bind to the C-terminal heptad repeat region of gp41 (HR2) and neutralize an HIV-1 primary isolate.

Description

[0001]This application is a U.S. National Stage Application of PCT Patent Application No. PCT / US2008 / 072764 filed Aug. 11, 2008 and claims benefit of priority to U.S. Provisional Patent Application Ser. No. 60 / 954,862 filed Aug. 9, 2007, the contents of each of which is are incorporated herein by reference in their entirety.[0002]This invention was made with support from the National Institutes of Health (Grant No. AI46383). The U.S. government may have certain rights in this present invention.BACKGROUND OF THE INVENTION[0003]The heptad repeat region 2 (HR2) of HIV-1 gp41 protein is involved in the formation of a coiled-coil structure with an N-terminal heptad repeat region on gp41 (HR1) that plays an important role in fusion. Binding of gp120 to the CD4 receptor results in a conformational rearrangement that is believed to expose portions of gp41 and initiate its rearrangement into a six helix bundle. An important role for this rearrangement in infection is indicated by the potent ...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K39/42A61K39/21C07K16/00
CPCA61K39/21C07K14/005C07K2319/02C07K2319/30C12N2740/16122C12N2740/16134A61K2039/54A61K2039/545A61K2039/55566A61K2039/575A61K39/12
Inventor PINTER, ABRAHAM
Owner RUTGERS THE STATE UNIV
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